This invention concerns the application of alternating electric fields and currents in patients or human subjects for the purpose of prevention of the formation of cancerous metastases and effecting or destroying metastases.
Living organisms proliferate by cell division, including tissues, cell cultures, microorganisms (such as bacteria, mycoplasma, yeast, protozoa, and other single-celled organisms), fungi, algae, plant cells, etc. Dividing cells of organisms can be destroyed, or their proliferation controlled, by methods that are based on the sensitivity of the dividing cells of these organisms to certain chemical or physical agents. For example, certain antibiotics stop the multiplication process of bacteria.
It is well known that tumors, particularly malignant or cancerous tumors, grow very uncontrollably compared to normal tissue. Such expedited growth enables tumors to occupy an ever-increasing space and to damage or destroy tissue adjacent thereto. Furthermore, certain cancers are characterized by an ability to spread metastases to new locations where the metastatic cancer cells grow into additional tumors.
The rapid growth of tumors and their metastases, in general, and malignant tumors in particular, as described above, is the result of relatively frequent cell division or multiplication of these cells compared to normal tissue cells. The distinguishably frequent cell division of cancer cells is the basis for the effectiveness of many existing cancer treatments, e.g., irradiation therapy and the use of various chemo-therapeutic agents. Such treatments are based on the fact that cells undergoing division are more sensitive to radiation and chemo-therapeutic agents than non-dividing cells. Because tumors cells divide much more frequently than normal cells, it is possible, to a certain extent, to selectively damage or destroy tumor cells by radiation therapy and/or chemotherapy. The actual sensitivity of cells to radiation, therapeutic agents, etc., is also dependent on specific characteristics of different types of normal or malignant cell types. Unfortunately, however, the sensitivity of tumor cells is not sufficiently higher than that of many types of normal tissues. This diminishes the ability to distinguish between tumor cells and normal cells, and therefore, existing cancer treatments typically cause significant damage to normal tissues, thus limiting the therapeutic effectiveness of such treatments. Also, certain types of tumors are not sensitive at all to existing methods of treatment.
Electric fields and currents have been used for medical purposes for many years. The most common is passing electric currents through portions of a human or animal body by application of an electric field using a pair of conductive electrodes between which a potential difference is maintained. These electric currents are used either to exert their specific effects, i.e., to stimulate excitable tissue, or to generate heat, since the body acts as a resistor. Examples of the first type of application include: cardiac defibrillators, peripheral nerve and muscle stimulators, brain stimulators, etc. Currents are used for heating, for example, in devices for tumor ablation, ablation of malfunctioning cardiac or brain tissue, cauterization, and relaxation of muscle rheumatic pain and other pain, etc.
Another use of electric fields for medical purposes involves the utilization of high frequency oscillating fields transmitted from a source that emits an electric wave, such as an RF wave or a microwave source, which is directed at the part of the body that is of interest (i.e., a target region). In these instances, no electric energy is transferred by conduction between the source and the body; but rather, the energy is transmitted to the body by radiation or induction. More specifically, the electric energy generated by the source reaches the vicinity of the body via a conductor and is transmitted from it through air or some other electric insulating material to the body.
Electric fields that can be used in medical applications can thus be separated generally into two different modes. In the first mode, the electric fields are applied to the body or tissues by means of conducting electrodes. These electric fields can be separated into two types, namely (1) steady fields or fields that change at relatively slow rates, and alternating fields of low frequencies that induce corresponding electric currents in the body or tissues, and (2) high frequency alternating fields (above 1 MHz) applied to the body by means of the conducting electrodes or by means of insulated electrodes.
The first type of electric field is used, for example, to stimulate nerves and muscles, pace the heart, etc. In fact, such fields are used in nature to propagate signals in nerve and muscle fibers, central nervous system (CNS), heart, etc. The recording of such natural fields is the basis for the ECG, EEG, EMG, ERG, etc. The field strength in conductive electrode applications, assuming a medium of homogenous electric properties, is simply the voltage difference applied to the stimulating/recording electrodes divided by the distance between them. The currents thus generated can be calculated by Ohm's law and can have dangerous stimulatory effects on the heart and CNS and can result in potentially harmful ion concentration changes. Also, if the currents are strong enough, they can cause excessive heating in the tissues. This heating can be calculated by the power dissipated in the tissue (the product of the voltage and the current).
When such electric fields and currents are alternating, their stimulatory power, on nerve, muscle, etc., is an inverse function of the frequency. At frequencies above 1-10 KHz, the stimulation power of fields approach zero. This limitation is due to the fact that excitation induced by electric stimulation is normally mediated by membrane potential changes, the rate of which is limited by the RC properties (time constraints on the order of 1 ms) of the membrane.
Regardless of the frequency, when such current inducing fields are applied, they are often associated with harmful side effects caused by currents. For example, one negative effect is the changes in ionic concentration in the various “compartments” within the system, and the harmful products of the electrolysis taking place at the surface of conducting electrodes and the release of toxic substances into the tissues or the medium in which the tissues are imbedded.
At one time, it was commonly believed that alternating fields of medium frequencies (about 50 kHz-1 MHz), had no biological effect except due to heating. Such fields can be applied to a conductive medium, such as a human body, via insulated electrodes. Under such conditions the electrodes induce in the body only capacitive currents. In contrast to the general belief that such fields have no direct biological effect, in U.S. patent applications Ser. Nos. 10/204,334 and 10/285,313, and in U.S. Pat. Nos. 6,868,289 and 7,016,562, each of which is incorporated herein by reference, such fields, termed “TTFields,” were shown to specifically target cancer cells for destruction. See also E. D. Kirson et al., Disruption of Cancer Cell Replication by Alternating Electric Fields, Cancer Research 64, 3288-3295, May 1, 2004, which is also incorporated herein by reference.
The present invention is designed to extend the use of TTFields to the prevention of the formation and elimination of established metastases as well as for the prevention of the development of cancers in subjects at risk.